Anilic acids of 3-substituted 2,4,6-triiodoanilines

ABSTRACT

CYCLIC IMIDES AND ANILIC ACIDS OF 2,4,6-TRIIODOANILINES BEARING A SUBSTITUTED AMINO GROUP IN THE 3-POSITION ARE PREPARED BY DECARBOXYLATION OF THE CORRESPONDING COMPOUNDS BEARING A CARBOXYL GROUP IN THE 5-POSITION. THE PRODUCTS ARE USEFUL AS INTERMEDIATES AND AS CHOLECYSTOGRAPHIC AGENTS.

United States Patent 3,803,221 ANILIC ACIDS 0F S-SUBSTITUTED2,4,6-TRIIODOANIL1NES James H. Ackerman, Bethlehem, N.Y., assignor toSterling Drug Inc., New York, N.Y.

No Drawing. Application July 14, 1969, 'Ser. No. 841,604,

now Patent No. 3,660,408, which is a continuation-inpart of abandonedapplication Ser. No. 715,583, Mar. 25, 1968. Divided and thisapplication Sept. 16, 1971, Ser. No. 181,249

Int. Cl. C07c 103/32 US. Cl. 260-518 A 7 Claims ABSTRACT OF THEDISCLOSURE Cyclic imides and anilic acids of 2,4,6-triiodoanilinesbearing a substituted amino group in the 3-position are prepared bydecarboxylation of the corresponding compounds bearing a carboxyl groupin the 5-position. The products are useful as intermediates and ascholecystographic agents.

1 5 I 1- 5 I m )3 6 3 1 3 1 R N Y R N-C o-w-oooxw NV r I CO I R I Iwherein Y is a lower-alkylene group wherein 2 or 3 carbon atoms separatethe carbonyl groups, vinylene or a 1,3-propylene group wherein the2-carbon atom is replaced by O, S, S0 or S0 Y is a single bond vinyleneor an alkylene bridge having from one to eight carbon atoms or such agroup interrupted by from one to three identical members selected fromO, S, SO and S0 said members, when more than one, being separated by atleast two carbon atoms; R is (lower-alkanoyl)NH, (loweralkanoyl)- NI-ICH(lower-alkanoyl)N(lower-alkyl), (lower-alkoxy-lower-alkanoyl)NH,(lower-alkoxy-lower-alkanoyl)- N(lower-alkyl),

/CO Y\ N HOOCY'CO-NH, or HOOCY'CO-N-(lower-alkyl); R is hydrogen,lower-alkyl, or hydroxy-lower-alkyl; and R" is hydrogen or lower-alkyl.

In the above Formula A, Y stands for a lower-alkylene group wherein 2 or3 carbon atoms separate the carbonyl groups and thus can be an ethyleneor propylene group optionally substituted by lower-alkyl. The. group Ycan 3,803,221 Patented Apr. 9, 1974 have from two to six carbon atomsand includes such groups as CH CH CH CH CH CH (CH CH CH CH (CH CH -CH(CHCH(CH CH CH C H CH -CH( CH CH CH CH(CH )CH(CH )CH(CH --CH C(CH CH andthe like. Y also stands for a 2-oxoor 2-thia-1,3-propylene group havingfrom 2 to 4 carbon atoms, for example, CH OCH CH(CH )OCH(CH and thelike. The group Y in Formula B is not limited to a two or three carbonbridge but represents a single bond or a divalent bridge, as hereinabovedefined, having from one to eight carbons separating the carbonyl andcarboxyl groups, optionally interrupted by from one to three identicalmembers selected from O, S, SO and S0 The term interrupted means,

of course, interposed between carbon atoms and not in a terminalposition adjacent to the carbonyl groups.

When R in the above Formulas A and B stands for (lower-alkanoyl)NH,(1ower-alkanoyl)NHCI-I (loweralkanoyl)N(lower-alkyl),(lower-alkoxy-lower-alkanoyl) NH or(lower-alkoxy-lower-alkanoyl)N(lower-alkyl), the lower-alkanoyl grouphas from one to six carbon atoms thus including, for example, formyl,acetyl, propionyl, butyryl, isobutyryl, valeryl, caproyl, and the like.

When R stands for (lower-alkanoyl)N(lower-alkyl),(lower-alkoxy-lower-alkanoyl)N(lower-alkyl), or

HOOCY'CON lower-alkyl) and/or R stands for lower-alkyl, and/or R" standsfor lower-alkyl, the lower-alkyl group has from one to four carbonatoms, thus including, for example, methyl, ethyl, propyl, isopropyl,and butyl.

When R stands for (lower-alkoxy-lower-alkanoyl)NH or(lower-alkoxy-lower-alkanoyl)N(lower-alkyl), the lower-alkoxy groupshave from one to four carbon atoms and thus include, for example,methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like.

The compounds of the invention of Formulas A and B above are prepared bydecarboxylation of compounds of Formulas C and D, respectively, asfollows:

wherein Y, Y, R, R and R" have the same meanings given hereinabove. Thedecarboxylation is carried out by heating a compound of Formula C or D,either in the free acid or salt form, in an organic solvent. A preferredmethod is heating the free acid or salt form, for example, the sodiumsalt, in dimethylformamide at a temperature between about and C.

The intermediate carboxylic acids of Formulas C and D are the subject ofmy copending application, Ser. N0.

3 808,653, filed Mar. 19, 1969, now US. Pat. 3,609,147 acontinuation-in-part of abandoned applications Ser. Nos. 550,614 and715,558, filed May 17, 1966, and Mar. 25, 1968, respectively, and areprepared as described below.

The method of preparation of the compounds of Formulas C and D variesaccording to the structure desired as follows:

(1) Compounds of Formula C where R is (lower-alkanoyl)NHCH,,(lower-alkanoyl)N(lower-alkyl), (lower-alkoxy-lower-alkanoyDN(lower-alkyl) f3 Y\ /N or HOOC--Y-CON(lower-alkyl) (a) Using a dibasicacid anhydride: A compound of the formula COOH wherein R has the meaninggiven above under (1), and Q is hydrogen or lower-alkanoyl, is heatedwith an acid anhydride of the formula a lower-alkylene group wherein 2or 3 carbon, atoms separate the carbonyl groups, in an inert solvent.

(2) Compounds of Formula D where R is hydrogen (a) Where Y is within thescope of Y, and R" is hydrogen: These compounds can be prepared byalkaline hydrolysis of the corresponding compounds of Formula C. Thereaction takes place in aqueous solution under mild conditions, at roomtemperature. Under these conditions the amide linkage to the 3-aminogroup is unaffected.

(b) Where R is as given under method (1) above: These compounds can beprepared by reacting a compound of Formula E where Q is hydrogen with ahalf ester half acid chloride, ClCOY'CO-OR, in an inert solvent,affording a compound of Formula D where R" is lower-alkyl. Hydrolysis ofthe latter under mild alkaline conditions gives an anilic acid ofFormula D where R" is hydrogen.

(3) Compounds of Formulas C and D wherein R is (lower-alkanoyl)NH or(lower-alkoxy-lower-alkanoyl) NH These compounds can be prepared from3-amino-5- nitrobenzoic acid according to the following flow sheet:

(I) O OH ('3 0 0H 0 O a OzN N Hz G 0 (MN -N /Y 20 1 t/ ('30 OH (I) O OH)2 HzN -N Y OzN -NHC 0-Y-C 0 OH C O OH KICI:

HzN NHC 0-Y-O O OH l KICI: C 0 OH O 0 OH I I I I O0 HzN N Y HiN NH C0-Y-O 0 0H I O 0 I (C, R=H N) (DI R=H2N, RI and R"=H) Alkanoic AlkanoiclAnhydr-ide Anhydride C O OH )3 (lower-alkanoyDNH -N\ /Y I CO (I) 0 OH II (lower-alkanoyl) NH NH0 0 -Y0 O 0 H 3-amino-5-nitrobenzoic acid isreacted with an anhydride, O(CO) Y, to give the cyclic imide (F). Thelatter can either be hydrogenated under acid or neutral conditions togive the amino cyclic imide (G) or hydrolyzed under basic conditions togive the corresponding nitroanilic acid (H). The nirroanilic acid inturn can be hydrogenated to the amino-anilic acid (I). Iodination of theamino cyclic imide (G) affords a compound of Formula C where R is H N,and iodination of the aminoanilic acid (J) gives a compound of Formula Dwhere R is H H and R is H. The primary amino groups can then, ifdesired, be acylated with a lower-alkanoic acid anhydried orlower-alkoxy-lower-alkanoic acid anhydride to give, respectively, acompound of Formula C where R is (lower-alkanoyl)NH or(lower-alkoxy-lower-alkanoyl) NH, or a compound of Formula D where R is(loweralkanoyl)NH or (lower-alkoxy-lower-alkanoyl)NH and R is hydrogen.

(4) Compounds of Formulas C and D where the groups in the 3- and5-positions are identical These are most conveniently prepared from3,5-diamino-2,4,6-triiodobenzoic acid. The latter is reacted with atleast two equivalents of an anhydride, O(CO) Y, to afford a compound ofFormula C where R is Y(CO) N, which then can be hydrolyzed to a compoundof Formula D where R is HOOC-YCONH and R and R" are H. The startingmaterial can also consist of a3-lower-alkanoylamino-5-amino-2,4,6-triiodobenzoic acid or a 3,5-bis(lower-alkanoylamino)benzoic acid. In the reaction with the anhydridethe lower-alkanoyl groups are replaced by cyclic imide groups.Alternatively, a method analogous to method (2)(b) above can be used,i.e., reacting 3,5- diamino-2,4,6-triiodobenzoic acid with a half esterhalf acid chloride ClCOY'COOR", affording a compound of Formula B whereR is R"OCOY'CONH, R is H and R" is lower alkyl.

(5) Compounds of Formula D wherein R is lower-alkyl orhydroxy-lower-alkyl These compounds can be prepared by N-alkylation ofthe corresponding compounds where R is hydrogen. The alkylation iseffected by the action of a lower-alkyl or hydroxy-lower-alkyl halide,sulfate, alkylsulfonate or arylsulfonate in the presence of aqueousalkali. If the starting material is a compound of Formula D where R is(loweralkanoyl)NH or HOOCY'CONH, alkylation occurs on both nitrogenssimultaneously.

The compounds of the invention where Y and/or Y are alkylene groupsinterrupted by S0 or S0 can alternatively be prepared by oxidation ofthe corresponding sulfide (-S) compounds with a peracid or hydrogenperoxide. The reaction takes place at room temperature in an inertorganic solvent.

Alternatively, the compounds of Formulas A and B can be prepared fromcompounds of the formula:

R NHQ (K) wherein R is H N, (lower-alkanoyl)NH, (lower-alkanoyl)NHCHlower-alkanoyl)N(lower-alkyl), (loweralkoxy-lower-alkanoyl) N(lower-alkyl) 00 Y N \;G

or HOOCYCON(lower-alkyl), where Y has the meaning given hereinabove, andQ is hydrogen or loweralkanoyl, by formation of the cyclic imides andanilic acids by methods analogous to those described above for thepreparation of compounds of Formulas C and D. The compounds of Formula Kare in turn prepared by decarboxylation of the compounds of Formula E,orby other procedures known in the art as illustrated by the specificexamples hereinbelow.

The structures of the compounds of the invention were determined by themodes of synthesis, by elementary analysis and by neutral equivalentdeterminations. The course of the reactions was followed by thin-layerchromatography.

Those compounds of the invention which are carboxylic acids can beobtained in the form of salts derived from inorganic bases or organicamines. Preferred salts are those which are pharmaceutically acceptable,for example, the sodium, magnesium, calcium and N-methylglucamine salts;although all salts are useful either as characterizing derivatives or asintermediates in the purification of the acids.

The compounds of the invention having the Formula A wherein R isHOOCY'CONH or (lower-alkyl), and the compounds of the invention havingthe Formula B are useful as X-ray contrast media for visualization ofthe gallbladder (cholecystography). The compounds have intraveoustoxicity (approximate LD values) in the range between 600 and 7500mg./kg. in mice. The compounds of lesser toxicity, LD =1500 mg./kg. orgreater, are primarily useful, in the form of their water-soluble,pharmaceutically acceptable salts, as intravenous cholecystographicagents. The compounds having LD values less than about 1500 mg./kg. areprimarily useful, either in the free acid or salt form, as oralcholecystographic agents.

The actual quantitative determination of toxicity and radiopaqueeffectiveness for a particular compound is readily determined bystandard test procedures by technicians trained in pharmacological testprocedures, without the need for any extensive experimentation.

The compounds were tested for their intraveous cholecystographicefiicacy by standard procedure as follows: The test compound wasinjected intravenously in the form. of an aqueous solution of the sodiumor N-methylglucamine salt to cats. Each cat was X-rayed at selected timeintervals and the roentgenograms examined and evaluated. The density ofthe gallbladder shadows was inte preted in accordance with a numericalscoring plan des-- ignated as the Cholecystographic Index (CI), ameasure of the efiiciency of the test compound, viz.: 0 (none), 1(poor), 2 (fair), 3 (good), 4 (excellent) [see J. O. Hoppe, J. Am.Pharm. Assoc., Sci. Ed. 48, 368-79 (1959)].

In testing for oral cholecystography, the test compound was administeredorally in capsules to each of five cats. About eighteen hours later,each cat was X-rayed and the roentgenograms were examined. The densityof the gallbladder shadow evoked by the test compound in each cat wasinterpreted in accordance with the above numerical scoring plan and theAverage Cholecystographic Index (ACI) determined.

The compounds of the invention, upon testing for cholecystographiceffectiveness in cats at a dose of mg. kg., were found to producegallbladder shadows having a Cholecystographic Index of 3.04.0 either byoral or by intravenous administration.

The compounds of the invention are prepared for cholecystographic use bydissolving a pharmaceutically acceptable salt from in sterile aqueousmedium suitable for intravenous injection; or in capsule or in tabletform with conventional excipients for oral administration.

The compounds of Formula A, wherein R is (loweralkanoyl)NH,(lower-alkanoyl)NHCH (lower-alkanoyl)N(lower-alkyl), (lower-alkoxylower-alkanoyl)NH,

(lower-alkoxy-lower-alkanoyl) N (lower-alkyl) or are useful asintermediates, by hydrolytic cleavage, for the preparation of compoundsof Formula B.

The following examples will further illustrate the invention.

EXAMPLE 1 acid was converted to its sodium salt form, M.P. 288- 291 C.(dec.) when recrystallized from water.

(b) N,N'-(2,4,6 triiodo-m-phenylene)diglutarimide [A; R is (CH (CO) N, Yis CH CH CH ].A mixture of 89.10 g. of sodium3,5-bis(glutarimido)-2,4,6- triiodobenzoate and 400 ml. ofdimethylformamide was warmed at 85 C. for 20 minutes to eflfectsolution, and then heated at reflux temperature (BO-135 C.) for fourhours. The solution was cooled, and the solid product collected, washedwith dimethylformamide and acetone, and dried to constant weight (35.18g.). An additional 41.75 g. of product was obtained by diluting thefiltrate with water. The combined product was recrystallized from aceticacid, using activated charcoal for decolorizing purposes, to giveN,N'-(2,4,6-triiodom-phenylene)diglutarimide, colorless prisms, M.P.above 300 C.

N,N'-(2,4,6-triiodo-m phenylene)diglutarimide can also be prepared byreacting 3-amino-2,4,6-triiodoaniline (K; R is H N, Q is H),3-amino-2,4-triiodoacetanilide (K; R is H N, Q is COCH or3-acetamido-2,4,6-triiodoacetanilide (K; R is CH CONH, Q is COCH withglutaric anhydride according to the procedure of Exam ple 1, part (a).

EXAMPLE 2 (a) 3-glutarimido-5 (N-methylacetamido)-2,4,6-triiodobenzoicacid [C; R is CH CON(CH Y is CH CH CH ].A mixture of 117.2 g. of3-amino-5- (N-methylacetamido)-2,4,6-triiodobenzoic acid and 182 g. ofglutaric anhydride was heated with stirring on a steam bath.Concentrated sulfuric acid (10 ml.) was added, and heating and stirringwere continued for seven hours. The reaction mixture was added to 700ml. of water, and the solid product was collected by filtration andrecrystallized from acetic acid. The resulting 3-glutarimido-5(N-methylacetamido)-2,4,6-triiodobenzoic acid was converted to itssodium salt form as follows: the free acid was slurried with 40 ml. ofmethanol and a 1 N solution of sodium hydroxide in methanol was addedwith trituration until the solid had dissolved. The sodium salt wasprecipitated out with ether, and the resulting gum was triturated withether and dissolved in methanol. The latter solution was decolorizedwith activated charcoal and the product reprecipitated with ether. Theproduct was dissolved in water and the solution filtered andconcentrated in vacuo. The residue was dried in vacuo to give the sodiumsalt of il-glutarimido-S-(N-methylacetamido) 2,4,6-triiodobenzoic acidas a pale pink solid, M.P. ZOO-204 C. (dec.).

(b) N-[2,4,6-triiodo-3 (N-methylacetamido)phenyl] glutarimide [A; R isCH CON(CH Y is CH CH CH can be prepared by decarboxylation of sodium3-glutarimido-S-(N-methylacetamido) 2,4,6-triiodobenzoate according tothe procedure of Example 1(b); or by decarboxylation of3-acetamido-5-(N-methylacetamido)-2, 4,6-triiodobenzoic acid followed byreacting the resulting 3-(N-methylacetamido)-2,4,6-triiodoacetanilide[K; R is CH CON(CH Q is COCH with glutaric anhydride.

By replacing the 3-amino-5-(N-methylacetamido)-2,4, 6-triiodobenzoicacid in the foregoing preparation by a molar equivalent amount ofB-amino-S-(N-butylacetamido)-2,4,6-triiodobenzoic acid,3-amino-5-(N-methylpropionamido)-2,4,6-triiodobenzoic acid,3-amino-5-(N- methylcaproylamino)-2,4,6-triiodobenzoic acid, 3-amino-5-(N,N-dimethylcarbamoyl)-2,4,6-triiodobenzoic acid, or3-amino-5-(N-methyl 2 methoxyacetamido)-2,4,6-triiodobenzoic acid, therecan be obtained, respectively, 3- glutarimido-S-(N-butylacetamido)2,4,6-triiodobenzoic acid [C; R is CH CON(C H Y is CH CH CH 3-glutarimido-S (N-methylpropionamido) 2,4,6-triiodobenzoic acid [C; R isCH CH CON(CH Y is CH CH CH 3-glutarimido-5-(N-methylcaproylamino)-2,4,6-triiodobenzoic acid [C; R is CH (CH CON(CH Y is CH CH CH3-glutarimido-5-(N,N-dimethylcarbamoyl)-2,4,6-triiodobenzoic acid [C; Ris (CHQ NCO, Y is CH CH CH or 3-glutarirnido-5-(N-methyl-Z-methoxyacetarnido)-2,4,6-triiodobenzoic acid [C; R is CH OCH CON(CH Y isCH CH CH which in turn can be decarboxylated to give, respectively,N-[2,4,6-

8 triiodo-3-(N-butylacetamido)phenyl]glutarimide [A; R is CH CON(C H Yis CH CH CH N-[2,4,6-triiodo- 3-(N-methylpropionamido)phenyllglutarimide[A; R is CH CH CON(CH3), Y is CH CH CH N-[2,4,6-triiodo-3-(Nmethylcaproylamino)phenyl] glutarimide [A; R is CH (CH CON(CH Y is CH CHCH N-[2,4, 6-triiodo 3-(N,N dimethylcarbamoyhphenyl]glutarimide [A; R is(CH NCO, Y is CH CH CH L or N-[2, 4,6-triiodo-3(N-methylmethoxyacetamido)phenyl] glu-' tarimide [A; R is CH OCH CON(CHY is CH CH CH EXAMPLE 3 (a) 3-succinimido 5(N-methylacetamido)-2,4,6-triiodobenzoic acid [C; R is CH CON(CH Y is CHC-H was prepared from 87.9 g. of3-amino-5-(N-methylacetamido)-2,4,6-triiodobenzoic acid, 120 g. ofsuccinic anhydride and 6 m1. of sulfuric acid according to the procedureof Example 2, except that a reaction temperature of 130-140" C. wasused. The reaction was essentially complete after minutes heating time.The compound was isolated in the form of its sodium salt, pale yellowsolid, M.P. 220-222 C. (dec.).

(b) N[2,4,6-triido 3 (N-methylacetamido)phenyl] succinimide [A; R is CHCON(CH Y is OHgCHz] can be prepared by heating sodiumS-SuccinimidO-S-(N-methylacetamido)-2,4,6-triiodobenzoate indimethylformamide by the method described in Example 1(b).

EXAMPLE 4 (a) 3(3-methylglutarimido)-5 (N-methylaeetamido)-2,4,6-triiodobenzoic acid [C; R is CH CON(CH Y is CH CH(CH )C-H wasprepared from 3-amino-S-(N- methylacetamido) 2,4,6 triiodobenzoic acid,3-methyl glutaric anhydride and sulfuric acid according to the procedureof Example 2. The product was isolated in the the free acid form, M.P.301-302 C. (dec.) when recrystallized from acetic acid.

(b) N-[2,4,6-triiodo-3-(N methylacetamido)phenyl] -3-methylglutarimide[A; R is CH CON(CH Y is CH CH(CH )CH can be prepared by heating sodium3-succinimido 5 (N methylacetamido)-2,4,6-triiodobenzoate indimethylformamide by the method described in Example 1(b).

The following compounds were prepared following the procedure of Example1 from the appropriate 3-amino- 5-R-2,4,6-triiodobenzoic acid and acidanhydride:

EXAMPLE 5 3-(3,3-dimethylglutarimido)-5 (N-methylacetamido)-2,4,6-triiodobenzoic acid [C; R is CH CON(CH Y is CH C(OH OH pale tansolid, M.P. 274-278 C. (dec.) (from acetic acid); sodium salt form, paleyellow solid, M.P. 235-24S C. (dec.).

EXAMPLE 6 3-gl utarimido 5 (N ethylacetamido)-2,4,6-triiodobenzo1c acid[C; R is CH CON (C 11 Y is CH CH CH sodium salt form, M.P. above 220 C.

EXAMPLE 7 3-(methylsuccinimido) 5 (N methylacetamido)-2,4,6-trnodobenzoic acid [C; R is OH CON(CH Y is 5 CH(CH3)CH2CH2], M.P.285-287 c. (from acetic acid); sodium salt form, M.P. above 245 C.(dec.).

EXAMPLE 8 I 3-(diglycolimido) 5 (N-methylacetamido)-2,4,6-triiodobenzoicacid [C; R is CH CON(CH Y is CH OCH sodium salt form, M.P. 250-255" C.N0 Sulfuric acid was used in this preparation,

9 EXAMPLE 9 3-(3,5 dioxothiomorpholino) 5 (Nmethylacetamido)-2,4,6-triiodobenzoic acid [C; R is CH CON (CH Y is CHSCH sodium salt form, beige solid, M.P. 250- 260 C. (dec.). No sulfuricacid was used in this preparation.

The compounds of Examples 5, 6 and 7 can be decarboxylated by the methodof Example 1(b) to produce, respectively, N-[2,4,6-triiodo 3(N-methylacetamido) phenyl]-3,3-dimethylglutarimide [A; R is OH CON (CHY is CH C(CH CH N-[2,4,6-triiodo 3 (N-ethylacetamido)phenyl] glutarimide[A; R is CH CON(C H Y is CH OH CH andN-[2,4,6-triiodo-3-(N-methylacetamido) phenyl1methylsuccinimide [A; R isCH CON(CH Y iS The compounds of Examples 8 and 9 were decarboxylated byheating the free acid forms in dimethylformamide, 90 minutes at refluxtemperature. There was obtained, respectively, N-[2,4,6-triiodo 3(N-rnethylacetamido)phenyl]diglycolimide [A; R is CH CON(CH Y is CH OCHM.P. 264-266 C. (from dimethylformamide); and 4-[2,4,6-triiodo 3(N-methylacetamido)- phenyl] -3,5-thiamrpholinedione [A; R is CH CON(OHY is CH SCH beige solid, M.P. 283-285" C. (from acetaic acid). Thelatter two compounds were also prepared by heating together at 120-150"C. equal weights of 2,4,6-triiodo-3-(N-methylacetamido)-aniline anddiglycolic anhydride or thiodiacetic anhydride, respectively.

3 (3,5 dioxothiomorpholino) (N methylacetamido)-2,4,6-triiodobenzoicacid can be oxidized with m-chloroperbenzoic acid in dimethylformamidesolution to give3-(3,5,S,S-tetraoxothiomorpholino)-5-(N-methylacetamido)-2,4,6-triiodobenzoicacid [C; R is CH CON (CH Y is OH SO CH2], which can be decarboxylatedaccording to the procedure of Example 1(b) to give 4-[2,4,6-triiodo-3-(N methylacetamido)phenyl] 3,5,S,'S tetraoxothiomorpholine [A;R is CH CON(CH Y is CH SO CH EXAMPLE 10 (a) 3-carb0xy 5 (Nmethylacetamido)-2',4,'6- triiodoglutaranilic acid [D; R is CH CON(OH Rand R" are H, Y is CH CH CH ].-A mixture of 58.6 g. of3-amin0-5-(N-methylacetamido) 2,4,6 triiodobenzoic acid, 74 g. ofglutaric anhydride and 8 m1. of concentrated sulfuric acid was heated ona steam bath for five hours. The reaction mixture was poured into waterand the solid product collected by filtration. The product, consistingof 3-glutarimido-5-(N-methylacetamido)-2,4,6- triiodobenzoic acid(Example 2) was dissolved in excess dilute aqueous sodium hydroxide, andthe solution warmed for thirty minutes, then cooled and 3 N hydrochloricacid added slowly until precipitation was complete. The solid productwas collected and recrystallized first from acetone, then from aceticacid, and finally from water to give 3-carboxy 5 (N-methylacetamido)2,4,6-triiodoglutaranilic acid, colorless prisms, M.P. 188.8-196.0 C.

(b) 2,4,6-triiodo 3' (N-methylacetamido)glutaranilic acid [B; R is CHCON(CH R and R" are H, Y is CH CIH CH can be prepared by heating thedisodium salt form of 3'-carboxy-5'-(N-methylacetamido)-2,4,6-triiodoglutaranilic acid in dimethylformamide according to the procedureof Example 1(b).

10 EXAMPLE 11 (a) 3-carboxy 5 (N-methylacetamido) 2,4,6-triiodosuccinanilic acid [D; R is CH CON(OH -R and R are H, Y is CH CHwas prepared from 34.3 g. of 3-amino-5-(N-methylacetamido) 2,4,6triiodobenzoic acid, 82 g. of succinic anhydride and 5 ml. ofconcentrated sulfuric acid, followed by alkaline hydrolysis of theresulting 3-succinimido 5 (Nmethylacetamido)-2,4,6- triiodobenzoic acid,according to the method described in Example 10. The product wasrecrystallized from dilute ethanol and from a methanol-acetonitrilemixture and further purified by converting it to the diammonium salt bymeans of ammonium hydroxide in methanol, and then acidifying an aqueoussolution of the ammonium salt to regenerate the free acid. There wasthus obtained 3-carboxy 5 (N-methylacetamido) 2,4',6 triiodosuccinanilicacid. M.P. 275.0-2760" C. (dec.).

(b) 2,4,6 triiodo 3-(N-methylacetamid0)succinanilic acid [B; R is CHCON(CH R and R" are H, Y is C-H CH colorless prisms, M.P. 209-211 C.,was prepared from 37.81 g. of disodium 3-carboxy-5-(N-methylacetamido)-2,4,6-triiodosuccinanilate in ml. ofdimethylformarnide, 40 minutes at reflux. The mixture was acidified withhydrochloric acid and the product collected and recrystallized fromacetone.

Similarly, by warming in dilute aqueous sodium hydroxide, 3 glutarirnido5-(N-butylacetamido)-2,4,6-triiododbenzoic acid, 3 glutarimidoS-(N-methylpropionamido) 2,4,6 triiodobenzoic acid, S-glutarimido-S-(N-methylcaproylamino)-2,4,6-triiodobenzoic acid, or 3-glutarimido-5-(N-methyl-2-methoxyacetamido -2,4,6-triiodobenzoic acid can behydrolyzed, respectively, to 3'-carboxy 5'(N-butylacetamido)-2,4,6-triiodoglutaranilic acid [D; R is CH CON(C H Rand R" are H, Y is CH 'CH CH 3 carboxy 5'-(N-methylpropionamido)2,4,6-triiodoglutaranilic acid [D; R is CH CH CON (CH R and R" are H, Yis CH CH CH 3'-carboxy-5'-(N-methylcaproylamino)-2',4,6-triiodoglutaranilic acid [D; R is CH (CHCON(CH R and R are H, Y is CH CH CH or 3 carboxy 5(N-methyl-Z-methoxyacetamido)-2,4,6-triiodoglutaranilic acid [D; R is'CH OCH CON (CH R and R" are H, Y is CH CH CI-I and in turndecarboxylated to give, respectively, 3'-(N-butylacetamido)-2',-4,6-triiodoglutaranilic acid [B; R is CH CON(C H R and R are H, Y is CHCH CH 3'-(N-methylpropionamido)-2',4,6'-triiodoglutaranilic acid [B; Ris CH CH CON CH R and R" are H, Y is CH CH CH 3- (N -methylcaproylamino)-2,4,6'-triiodoglutaranilic acid [B; R is CH (CH CON(CH Rand R are H, Y' is or 3 (Nmethyl-Z-methoxyacetamido)-2,4,6'-trii0doglutaranilic acid [B; R is CHOCH CON(CH R and R are H, Y is CH CH CH 3 carboxy 5'(Nmethylacetamido)-2,4,6'-triiodoglutaranilic acid can also be preparedby heating 3-amino- 5-(N-methylacetamido)-2,4,6-triiodobenzoic acid with4- carbomethoxybutyryl chloride in dioxane solution, followed byhydrolysis of the resulting methyl 3 carboxy5-(N-methylacetamido)-2,4,6-triiodoglutaranilate by heating it withpotassium carbonate in methanol solution.

Similarly, 3 amino 5 (N-methylacetamido) -2,4,6-triiodobenzoic acid canbe caused to react with Cl'COCH CH OCH CH OCH CH OCH CH COOCH to give,respectively, the following compounds: [D; R is CH CON(CH3) R is H, R"is CH Y is [D; R is CH CON(CH R is H, R" is CH Y is CH CH OCH CH [D; Ris CH CON(CH R is H, R" is CH Y is CH CH OCH CH OCH OH OCH CH or [D; Ris CH CON(CH R is H, R" is CH Y' is CH SCH CH CH CH SCH These can behydrolyzed to the corresponding dibasic acids where R is hydrogen anddecarboxylated to give, respectively, the following compounds: [B; R isCH CON(CH R and R" are H, Y is CH CH CH CH [B; R is CH CON(CH R and Rare H, Y is CH CH OCH CH [B; R is CH CON(CH R and R" are H, Y is CH CHOC-H CH OCH CH OCH CH or [B; R is CH CON(CH R and R" are H, Y is CH SCHCH CH CH SCH The starting. half-ester half-acid chlorides are a knownclass of compounds readily prepared by partial hydrolysis of thecorresponding di-esters followed by reaction of the resultinghalf-esters with thionyl chloride.

In the same manner, 3,5-diamino-2,4,6-triiodobenzoic acid can be causedto react with Cl-COCH CH CH CH COOCH to give [D; R is CH OCOCH CH CH CHCONH, R is H, R" is CH Y is CH CH CH CH which can he hydrolyzed to give[D; R is HOCOCH CH CH CH CONH, R and R" are H, Y is CH CH CH CH and thelatter decarboxylated to give [B; R is R and R" are H, Y is CH CI-I CHCH EXAMPLE 12 (a) 3 [2 -'(carboxymethylsulfonyl)acetamido]-2,4,6-triiodo-S-(N-methylacetarnido)benzoic acid [D; R is CH3CON(CH3) R and Rare H, Y is CH SO CH ].A solution of 26.1 g. of3-amino-5-(N-methylacetamido)-2,4,6-trii0do benzoic acid in 300 ml. ofdioxane was distilled until about 60 m1. of dioxane was removed in orderto eliminate possible traces of water. Sulfonyldiacetyl chloride(CICOCHgSOgCHgCOCl) (5.85 g.) was then added, and the mixture wasstirred and refluxed for about five days. The reaction mixture wasconcentrated in vacuo to remove the solvent, and the residue wasdissolved in dilute sodium hydroxide to give a solution of the sodiumsalt of the product. The basic solution was made weakly acid, which didnot cause precipitation of the acid form of the product, treated withactivated charcoal at 60 C. and filtered. The filtrate was acidifiedwith 3 N hydrochloric acid and the precipitated product collected. Theacid product was purified by dissolving it in ammonium hyroxide solutionand reacidifying the resulting ammonium salt solution. The acid productwas recrystallized from aqueous dimethylformamide to give 3 [2(carboxymethylsulfonyl)acetamido]-2,4,6-triiodo-S-(N-methylaeetamido)benzoic acid, M.P. above 300 C.

(b) {N {2,4,6-triiodo-3-(N-methylacetamido)phenyl]carbamoylmethylsulfonyl}acetic acid [B; R is CH CON (CH R and R" are H,Y is CH S' CH can be prepared by decarboxylatiou of 3 [2(qarboxymethylsulfonyl)acet- 12amido]-2,4,6-triiodo-5-(N-methylacetamido)benzoic acid according to theprocedure of Example 1(b). The product is the same as that described inExample 20 below.

By replacing the sulfonyldiacetyl chloride in the foregoing preparationby sulfoxydiacetyl chloride (CICOCHz-SO-CHzCOCl) there can be obtained3-[Z-carboxymethylsulfoxy)acetamido] 2,4,6triiodo-5-(N-methylacetamido)benzoic acid [D; R is CH CON(CH R and R"are H, Y is CH SOC-H which can be decarboxylated to give {N- [2,4,6triiodo 3 (N methylacetamido)phenyllcarbamoylrnethylsulfoxy}acetic acid[B; R is CH CON(CH R and R" are H, Y is CH SOCH L The followingcompounds can be prepared either by mild alkaline hydrolysis of thecorresponding cyclic imides, or directly from the appropriate3-amino-5-R-2,4,6-triiodobenzoic acid without isolation of theintermediate cyclic imide, followed by decarboxylation of the resultinganilic acid, as described above in Examples 10 and 11.

EXAMPLE 13 (a) 3 carboxy-TA,6'-triiodo-3-methyl-5-(N-methylacetamido)glutaranilic acid [D; R is CH CON(CH R and R" are H,Y is CH CH(CH )CH colorless crystals, M.P. 256-259 C. (dec.).

(b) 2,4,6' triiodo-3-methyl-3'-(N-methylacetamido)- glutaranilic acid[B; R is CH CON(CH R and R" are H, Y is CH CH(CH )CH pale tan crystalsfrom aqueous acetic acid, M.P. 189-193 (1.; sodium salt form, beigepowder from methanol-ether, M.P. 202204 C.

EXAMPLE 14 (a) 3,5 -bis(4-carboxybutyramido)-2,4,6-triiodobenzoic acid[D; R is HOOC(CH CONH, R and R" are H, Y is CH CH CH colorless solid,M.P. 251-253 C. (from acetic acid).

(b) N,N' (2,4,6 triiodo-m-phenylene)diglutaramic acid [B; R is HOOC(CHCONH, R and R" are H, Y' is CHZCHQCHB]: colorless prisms from aceticacid, M.P. 278-279 C. [prepared by hydrolysis ofN,N'-(2,4,6-triiodo-m-phenylene)diglutarirnide (Example 1b) with so diumhydroxide in acetone solution two hours at reflux].

EXAMPLE 15 (a) 3 carboxy 2,4,6' triiodo-3,3-dimethyl-5-(N-methylacetamido)glutaranilic acid [D; R is CH CON(CH R and R" are H, Y,is CH C(CH CH], colorless crystals, M.P. 258-262 C. (dec.).

(b) 2,4,6' triiodo 3,3 dimethyl-3'-(N-methylacetamido) glutaranilic acid[B; R is CH CON(CH R and R" are H, Y is CH C(CH CH tan powder, M.P. 132-134 C.

EXAMPLE 16 (a) 3 carboxy 5 (N-ethylacetamido)-2,4,6'-triiodoglutaranilicacid [D; R is CH CON(C H R and R" are H, Y is CH CH CH colorless solid,M.P. 250 C. (dec.).

(b) 2',4,6-' triiodo 3' (N-ethylacetamido)glutaranilic acid [B; R is CHCON(C H R and R" are H, Y is CH2CH2CH2].

EXAMPLE 17 (a) 3' carboxy 2,4',6'triiodo-3-methyl-5'-(N-methylacetamido)succinanilic acid [D; R is CHCON(CH R and R" are H, Y is CI-I(CH )CH light orange solid, M.P. 262264C. (dec.).

(b) 2,4,6 triiodo 3 methyl-3'-(N-methylacetamido)succinanilic acid [B; Ris CH CON(CH R and R" are H, Y is CH(CH )CH 13 EXAMPLE 18 (a) 3 carboxy2',4,6' triiodo--(N -methylacetarnido)diglycolanilic acid [D; R is CHCON(CH R and R" are H, Y is CH OCH disodium salt form, light tan solid,M.P. 245260 C. (dec.).

(b) 2',4,6 triiodo 3' (N-methylacetamido)diglycolanilic acid [B; R is CHCON(CH R and R" are H, Y' is CH OCH colorless solid, M.P. 125-133 C.

EXAMPLE 19 (a) 3 [2(carboxymethylthio)acetamido]-2,4,6-triiodo-S-(N-methylacetamido)benzoicacid [D; R is CH CON (CH R and R are H, Y is CH SCH beige solid, M.P.165- 170 C.

(b) {N [2,4,6 triiodo-3-(N-methylacetamido)phenyl]carbamoylmethylthio}acetic acid [B; R is CH CON(CH R and R" are H, Y isCH SCH EXAMPLE 20 {N [2,4,6 triiodo-3-(N-methylacetamido)phenyl]carbamoylmethylsulfonyl}acetic acid [B; R is CH CON(CH R and R" are H, Yis CH SO CH {N [2,4,6 triiodo-3-(N-methylacetamido)phenyl]carbamoylmethylthio}acetic acid (derived by hydrolysis of 25.0 g. of4-[2,4,6-triiodo-3-(N-methylacetamido)phenyl]- 3,5-thiamorpholinedione)was dissolved in 150 ml. of glacial acetic acid at 40 C. Hydrogenperoxide (72 ml. 30%) was added. After five minutes the mixture wasconcentrated to a volume of 75 ml. and 400 ml. of water added. Theproduct which separated was crystallized by stirring the mixture in ice,and was collected and dried to give {N- [2,4,6-triiodo-3-(N-methylacetamido) phenyl] carbamoylmethylsulfonyl}acetic acid, M.P.148150 C.

(dec.).

EXAMPLE 21 (a) 3-succinimido-S-nitrobenzoic acid [F; Y is CH CH wasprepared by heating 3-amino-5-nitrobenzoic acid with succinic anhydridein the presence of sulfuric acid. It had the M.P. 262-268 C. whenrecrystallized from aqueous dimethylformamide.

(b) 3-carboxy-S'-nitr0succinanilic acid [H; Y is CH CH was prepared bytreating 3-succinimido-5-nitrobenzoic acid with warm dilute aqueoussodium hydroxide, and had the M.P. 22022l C.

(c) 3'-carboxy-5'-aminosuccinanilic acid [J Y is CH CH3-carboxy-5'-nitrosuccinanilic acid (83.5 g.) and 50 ml. of concentratedammonium hydroxide in 100 ml. of water were added to a heated solutionof 540 g. of ferrous sulfate heptahydrate in 900 m1. of water.Concentrated am monium hydroxide (100 ml.) was then added during fifteenminutes in 50 ml. portions. After thirty minutes of heating on a steambath, the reaction mixture was filtered and made acid to pH 3.5. Theproduct was collected and dried in vacuo over phosphorus pentoxide togive 57.5 g. of 3'-carboxy-5-aminosuccinanilic acid, M.P. 194 C. (dec.).

(d) 3' carboxy-5-amino 2',4,6 triiodosuccinanilic acid [D; R is NH R andR are H, Y is CH CH Potassium iododichloride (335 ml. 2.23 N in water),was added over a period of forty minutes to a stirred suspension of 57.3g. of 3-carboxy-5-aminosuccinanilic acid in 435 ml. of water. The solidproduct was collected by filtration and recrystallized from water andfrom aqueous dimethylformamide. The product was purified by convertingit to the diammonium salt and then to the disodium salt, M.P. 222-225"C. (dec.). The latter was acidified to produce the free acid form of3-carboxy-5-amino-2',4,6- triiodosuccinanilic acid, cream colored solid,M.P. 156.2- 172.2 C. (dec.).

3 carboxy-5-amino-2,4',6'-triiodosuccinanilic acid can be acylated withacetic anhydride, using a few drops of perchloric acid as a catalyst toobtain 3'-carboxy-5- acetamido-2,4',6'-triiodosuccinanilic acid [D; R isCH CONH R and R" are H, Y is CH CH which can be decarboxylated accordingto the method of Example 1(b) to give 2,4,6'triiodo-3-acetamidosuccinanilic acid [B; R is CH CONH, R and R" are H, Yis CH CH EMMPLE 22 (a) 3-glutarimido-5-nitrobenzoic acid [F; Y is CH CHCH was prepared by heating a mixture of 18.2 g. of 3-amino-5-nitrobenzoic acid, 45.6 g. of glutaric anhydride and 0.5 ml. ofconcentrated sulfuric acid on a steam bath for two hours. The productwas isolated and recrystallized from aqueous dimethylformamide to give3-glutarimido-5-nitrobenzoic acid, pale yellow prisms, M.P. above 300 C.

(b) 3 glutarimido 5 aminobenzoic acid [6; Y is CH CH CH can be preparedby reduction of 3-glutarimido-5-nitrobenzoic acid. The reduction can becarried out catalytically (platinum or nickel catalyst) under neutral oracidic conditions.

(c) 3-glutarimido-5-amino 2,4,6 triiodobenzoic acid [C; R is H N, Y isCH CH CH can be prepared by iodination of 3-glutarimido 5 aminobenzoicacid with potassium iododichloride according to the procedure describedin Example 21, part (d).

(d) 3-glutarimido-5-acetamido 2,4,6 triiodobenzoic acid [C; R is CHCONH, Y is CH CH CH can be prepared by acetylation of3-glutarimido-5-amino-2,4,6-triiodobenzoic acid with acetic anhydride,using a few drops of perchloric acid as a catalyst.

(e) 2,4',6'-triiodo-3 acetamidoglutaranilic acid [B; R is CH CONH, R andR are H, Y is CH CH CH can be prepared by hydrolysis and decarboxylationof 3- glutarimido 5 acetamido 2,4,6 triiodobenzoic acid.

Alternatively, 3-glutarimido-5-amino-2,4,6-triiodobenzoic EXAMPLE 23 (a)3'-carboxy-5-amin0-2,4,6 triiodo N methylglutaranilic acid [D; R is H N,R is CH R" is H, Y' is CHzCHzOHg].

To a solution of 26.0 g. of 3'-carboxy-5'-amino-2,4,-6-triiodoglutaranilic acid [prepared by hydrolysis of 3-glutarirnido-5-amino-2,4,6 triiodobenzoic acid (Example 22c)] in m1. of10% aqueous sodium hydroxide cooled in an ice bath was added 8 ml. ofdimethyl sulfate in acetone. After three hours of stirring an additional15 ml. of 10% sodium hydroxide and 2 ml. of dimethyl sulfate were addedand the mixture stirred three hours longer. The reaction mixture wasacidified, and the product collected and recrystallized from acetic acidto give 3'-carboxy-5-amino-2',4,6 triiodo N methylglutaranilic acid,pale gray crystals, M.P. 2l8-220 C. (dec.).

(b) 3'-carboxy-5'-glutarimido-2,4,6'-triiodo-N-methylglutaranilic acid[C; R is HOOC(CH CON(CH Y is CH CH CH was prepared from 3' -carboxy-5'-amino-2',4',6-triiodo-N-methylglutaranilic acid and glutaric anhydrideaccording to the procedure of Example 1. The free acid was obtained as acolorless solid, M.P. l60161 C. when recrystallized from acetic acid,and the disodium salt form as a beige solid, M.P. 252-255 C.

(c) 3-glutarimido2',4',6' triiodo N methylglutaranilic acid [A; R isHOC(CH CON(CH Y is CH C-H CH was prepared from 29.65 g. of the disodiumsalt of 3'-carboxy5' glutarimido 2',46 triiodo N- methylglutaranilicacid in 70 ml. of dimethylformamide, 30 minutes at reflux. The free acidproduct was obtained in the form of a mauve powder, 256-257" (3.; sodiumsalt form, mauve powder, M.P. 241-245 C.

EXAMPLE 24 (a) 3'-carboxy-5'-(N-methylacetamido) 2',4',6'triiodo-N-methylglutaranilic acid [1); R is CH CON(CH R is CH R" is H,Y' is CH CH CH was prepared from 49.0 g. of3-carboxy-5-(N-methylacetamido)-2',4', 6'-triiodoglutaranilic acid(Example 10) and 15 ml. of dimethyl sulfate in 175 ml. of 10% sodiumhydroxide according to the procedure of Example 23. The product wasrecrystallized from acetic acid, using ethyl acetate to bring thecompound out of solution. There was thus obtained3'-carboxy-5-(N-methylacetamido) 2',4",6' triiodo-N-methylglutaranilicacid, colorless prisms, M.P. 284-287 C. (dec.).

(b) 2',4',6-triiodo-3' (N methylacetamido) N- methylgl utaranilic acid['B; R is CH CON(CHa), R is CH ER" is H, Y' is CH CH CH was preparedfrom 16.42 g. of the disodium salt of3-carboxy-5-(N-methylacetamido)-2,4',6'-triiodo-N methylglutaranilicacid in 40 ml. of dimethyl formamide, 30 minutes at reflux. The freeacid product was recrystallized from aqueous acetic acid and obtained aspale cream-colored crystals, M.P. 90-100" C.; sodium salt form, M.P.173-475 C.

\EXAMPLE 25 (a) 3'-carboxy-5-(N-methylacetamido) 2',4,6triiodo-N-ethylglutaranilic acid [D; R is CH CON(CH R is C H R" is H, Yis CH CH CH was prepared from 56.3 g. of 3'-carboxy-5-(N-methylacetamido)-2',4', 6'-triiodoglutaranilic acid (Example 10) and40 ml. of diethyl sulfate in 10% sodium hydroxide solution according tothe procedure of Example 23. The product was recrystallized from aceticacid and from an acetic acid-ethyl acetate mixture to give 3'-carboxy-5'(N methylacetamido)-2',4,6-triiodo N ethylglutaranilic acid, M.P. 25926lC. (dec.).

=(b) 2',4',6-triiodo-3' (N methylacetamido) N- ethylglutaranilic acid[B; R is CH CON(CH :R' is C 11 'R" is H, Y is CH CH CH was prepared from44.1 g. of the disodium salt of3-carboxy-S-(N-methylacetamido)-2',4',6'-triiodo-N-ethylglutaranilicacid in 107 ml. of dimethylformamide, 45 minutes at reflux. The producthad the M.P. 112-1125 C. when recrystallized from aqueous acetic acid.

3'-carboxy-5'-(N-methylacetamido) 2',4,6 triiodoglutaranilic acid cansimilarly be alkylated with n-butyl iodide or 2-hydroxyethyl bromide togive 3'-carboxy-5'- (N methylacetamido) 2',4',6 triiodo Nbutylglutaranilic acid [D; R is CH CON(CH R is C H R" is H, Y is CH CHCH or 3-carboxy-5'-(N-methylacetamido)-2,4',6'-triiodo-N (2hydroxyethyl)glutaranilic acid [D; R is CH CON(CH R is HOCH CH R" is H,Y is CH CH CH which in turn can be decarboxylated to give, respectively,2,4,6'-trii0do-3'-(N- methylacetamido) N butylglutaranilic acid [B; R isCH CON (CH R is C411 R" is H, Y is CH CH CH l, or 2',4',6- triiodo-3' (Nmethylacetamido) N (2- hydroxyethyl)glutaranilic acid [B; R is CH CON(CHR is .HoC zC z, R" is Y is CH CH CH 1 6 EXAMPLE 26 (a) 3-carboxy 2,4',6'triiodo 5' (N methylacetamido)-3,3,N-trimethylglutaranilic acid [D; R isCH OON (CH R is CH :R" is H, Y is CH C(CH CH M.P. 183- 184.5 C., wasprepared by methylation of 3'-carboxy-2', 4',6'-triiodo-3,3 dimcthyl 5'(N methylacetamido) glutaranilic acid (Example 1521) according to themethod of Example 23(a).

(b) 2',4',6-triiodo-3 (N methylacetamido) 3,3, N-trimethylgl-utaranilicacid [B; R is CH CON(CH R is CH R" is H, Y is CH C(CH CH beige powder,M.P. 119-122 C., was prepared by decarboxylation of3-carboxy-2',4',6'-triiodo-5' (N methylacetamido) 3,-3-N-trimethylglutranilic acid according to the method of Example 1(b).

The following compounds were prepared by the methylation procedure ofExample 23(a):

EXAMPLE 27 N,N (2,4,6 triiodo in pheny1ene)bis-(N-methylglutaramic acid)[B; R is HOOCOH CH CH CON(CH R is CH R" is H, Y' is OH CH CH disodiumsalt form, colorless prisms, M.P. 241245 C., by methylation of N,N'(2,4,6 triiodo-m-phenylene)diglutaramic acid (Example 14b).

EXAMPLE 2-8 2,4','6' triiodo 3 (N-methylacetamido) -N-methylsuccinanilicacid [B; R is CH CON(CH R is CH R" is H, Y is CH CH M.P. 199-200 C. fromaqueous acetic acid; sodium salt form, M.P. -190 C. from methanol-ether,by methylation of 2',4',6'-triiodo-3'-(N- methylacetamido)succinanilicacid (Example 11b).

EXAMPLE 29 2',4,6' triiodo 3 (Nmethylacetamido)-3,N-dimethylglutaranilic acid [B; R is CH CON(CH3), Ris CH R" is H, Y' is CH OH(CH )CH colorless powdery M.P. 101-1075 C., bymethylation of 2,4',6'-triiodo-3'- (N methylacetamido) '3methylglutaranilic acid (Example 13b).

EXAMPLE 30 {N Methyl N [2,4,6 triiodo 3 (N-methylacetamido) phenyl]carbamoylmethylthio}acetic acid [B; R is CH CON(CH R is CH;,, R" is H, Yis CH SCH l, tan solid, M.P. 124-129 0., prepared by hydrolysis of 4[2,4,6 triiodo 3 (N-methylacetamido)pheny1]-3, S-Uhiamonpholinedione andmethylation of the resulting {N [2,4,6 triiodo 3(N-methylacetamido)phenyl] carbamoylmethylthio}acetic acid.

EXAMPLE 31 2',4',6' triiodo 3'(N-methylacetamido)-N-methyldiglycolanilic acid [B; R is CH CON(CH R isCH 'R" is H, Y is CHgOCHg], colorless solid, M.P. l41-143 C., preparedby hydrolysis of N-[2,4,6-triiodo-3-(N-methylacetamido)phenylJdiglycoIimide, andmethylation of the resulting 2', 4,6"-triiodo-3-(N-methylacetamido)diglycolanilic acid.

EXAMPLE 32 (a) N,N (2,4,6 triiodo a,m toluylene)bis[acetamide] [K', R"is CH3CONHCH2, Q is COCH was prepared by decarboxylation ofS-acetamido-S-acetamidm methyl-2,4,G-triiodobenzoic acid according tothe method of Example 1(b), and was obtained in the form of a colorlesssolid, M.P. 287-288" C. when recrystallized from acetic acid.

(b) N [2,4,6 triiodo 3 (acetylaminomethyl) phenyllglutarimide [A; R isCH CONHCH Y is CH CH CH was prepared by interacting a-acetamido- 21,436triiodo m acetotoluidine with glutaric anhy- 1 7 dride according to themethod of Example 2(a), and was obtained in the form of a colorlesssolid, M.P. 128l34 C. when recrystallized from isopropyl alcohol.

IDLAMPLE 33 (a) N [2,4,6 triiodo 3 (acetylaminomethyl)-5-carboxyphenyl1glutarimide (C; R is CH CONHCH Y is C-H CH C-H wasprepared by interacting 3-acetamido S-acetamidomethyl-2,4,6-triiodobenzoic acid with glutaric anhydride according to the method ofExample 2( a), and was obtained in the form of a colorless solid, M.P.256- 258 C. when recrystallized from acetic acid.

(b) N [2,4,6 triiodo 3 (acetylaminomethyl) 5- carboxyphenyl1glutaramicacid [D; R is CH CONHCH R and R are H, Y is CH CH CH was prepared byhydrolysis of N-[2,4,6-triiodo-3-(acetylaminomethy1)-5-carboxyphenynglutarimide with dilute sodium hydroxide, and was obtainedin the form of a colorless solid, M.P. 234-239 C. when recrystallizedfrom acetic acid.

(c) N [2,4,6 triiodo-3(acetylaminomethyl)phenyl] glutaramic acid[B; R isCH3CONHCH2, R and R are H, Y is CH CH CH was prepared by decarboxylationof N [2,4,6 triiodo 3 (acetylaminomethyl)5-carboxyphenyHglutaramic acidaccording to the method of Example Nb), and was obtained in the form ofa colorless solid, M.P. 254-259 C. when recrystallized from aqueousdimethylformamide. The same substance can be prepared by hydrolysis of N[2,4,6 triiodo-3-(acetylaminomethyl)phenyl] glutarimide (Example 32b)with warm dilute sodium hydroxide.

EXAMPLE 34 N [2,4,6 triiodo 3 (acetylaminomethyl)phenyl]-N-methylglutaramic acid [B; R is CH CON'HCH R is CH R" is H, Y is CH CHCH was prepared by interacting N [2,4,6triiodo-3-(acetylaminomethyl)phenyl] glutaramic acid (Example 33c) withdimethyl sulfate according to the procedure of Example 23, and wasobtained in the form of a colorless solid, M.P. 167-175 C. whenrecrystallized from ethyl acetate.

EXAMPLE 35 (a) Methyl 3' carboxy 2,4,6 triiodo 5' (N-methylacetamido)azelanilate [D; R is CH CON(CH R is H, R is CH Y is -(CHA mixture of 100 g. of azelaic acid monomethyl ester and 500 ml. ofthionyl chloride was refluxed for one hour. The excess thionyl chloridewas removed by distillation and the last traces removed by addingbenzene and evaporating the solvent. A solution of 260g. of 3-amino-5-acetamido-2,4,6- triiodobenzoic acid in 3500 ml. of dioxane was thenadded to the resulting acid chloride of azelaic acid monomethyl ester,and the mixture was refluxed for six hours. The dioxane was then removedby distillation and the residual product recrystallized from acetic acidto give methyl 3-carboxy-2',4,6-triiodo-5-(N-methylacetamido)azelanilate, as colorless needles, M.P. 198-203 C.

By replacing the azelaic acid monomethyl ester by a molar equivalentamount of oxalic acid monomethyl ester or malonic acid monomethyl ester,there can be obtained, respectively, methyl 3 carboxy2,4,6-triiodo-5-(N- methylacetamido)oxalanilate [D; R is CH CON(CH R isH, R" is CH Y is single bond], or methyl 3'-carboxy 2,4',6'triiodo-5-(N-methylacetamido)malonanilate [D; R is CH CON(CH R is H, Ris CH Y is CH;;-].

-(b) 3' carboxy 2,4',6' triiodo 5 (N methylacetamido) azelanilic acid[D; R is CH CON(CH R and R are H, Y is (C-H A mixture of 136.5 g. ofmethyl 3-carboxy-2,4',6- triiodo 5' (N-methylacetamido)azelanilate and180 ml. of water was treated with 10% aqueous sodium hydroxide (about140 ml.), added dropwise until solution was complete. The mixture washeated on a steam bath for ten minutes, 18 ml. more of 10% sodiumhydroxide was added, and the mixture heated one hour longer. Thereaction mixture was cooled, acidified with 3% hydrochloric acid, andthe solid product collected, washed with water, dried and recrystallizedfrom acetic acid to give 3' carboxy 2,4,6'-triiodo 5-(N-methylacetamido) azelanilic acid as a colorless solid, M.P. 205208C.

By replacing the methyl 3'-carboxy-2,4,6-triiodo-5-(N-methylacetamido)azelanilate by a molar equivalent amount of methyl3-carboxy-2',4, 6-triiodo-5'-(N-methylacetamido)oxalanilate or methyl3-carboxy-2,4,6- triiodo-5-(N-methylacetamido)malonanilate there can beobtained, respectively, 3' carboxy 2',4',6 triiodo-5'-(N-methylacetamido) oxalanilic acid [D; R is CH CO-N (CH R and R are H,Y is single bond] or 3-carboxy-2,4,6- triiodo 5(N-methylacetamido)malonanilic acid [D; R is CH CON(CH R and R" are H, Yis -C-H (c) 2,4,6 triiodo-3'-(N-methylacetamido)azelanilic acid [B; R isCH CON(CH R and R are H, Y, is (CH was prepared by decarboxylation of3-carboxy- 2,4,6 triiodo-5-(N-methylacetamido) azelanilic acid accordingto the method of Example 1(b), and was obtained in the form of acolorless solid, M.P. 1S3- 160 C.

By replacing the 3-carboxy-2,4,6-triiodo-5-(N-methylacetamido)azelanilicacid by a molar equivalent amount of 3-carboxy 2,4,6triiodo-5'-(N-methylacetamido) oxalanilic acid and3-carboxy-2',4',6-triiodo-5-(N-methylacetamido)malonanilic acid therecan be obtained, respectively, 2,4,6'triiodo-3-(N-methylacetamido)oxalanilic acid [B; R is CH CONH(CH R and Rare H, Y is single bond] or2,4,6'-triiodo-3-(N-methylacetamido)malonanilic acid [B; R is CH CONH(CHR and R are H, Y is CH Alternatively,2,4,6-triiodo-3-(N-methylacetamido)- azelanilic acid can be prepared byinteracting 3-amin0-2, 4,6-triiodo-N-methylacetanilide [K; R is CH CONCH Q is H] with the acid chloride or azelaic acid monomethyl ester, andsubjecting to mild alkaline hydrolysis the resulting methyl 2',4,6triiodo-5-(N-methylacetamido)azelanilate 1B; R is CH CON(CH R is H, R"is CH3, Y iS (cH2)q].

(d) 2,4,6 triiodo-N-methyl-3-(N-methylacetamido) azelanilic acid [B; Ris CH CON(CH3), R is CH R" is H, Y is ---(CH:,,) was prepared bymethylation of 2,4,6 triiodo-3'-(N-methylamido)azelanilic acid withdimethyl sulfate according to the procedure of Example 23, and wasobtained in the form of its sodium salt, colorless solid, M.P. above C.

EXAMPLE 36 (a) N-methyl-N,N-(2,4,6-triiodo m phenylene)bis [acetamide][K; R is CH CON(CH Q is COCH was prepared by decarboxylation of3-acetamido-5-(N- methylacetamido)-2,4,6-triiodobenzoic acid accordingto the procedure of Example 1(b), and was obtained in the form of acolorless solid, M.P. C.

(b) S-maleimido 2,4,6 triiodo-N-methylacetanilide [A; R is CH CON(CH Yis CH=CH--] can be prepared by interacting 2,4,6triiodo-N-methyl-m-benzenediacetamide with maleic anhydride according tothe procedure of Example 2(a), or by decarboxylation of 2, 4,6-triido 3maleimido-S-(N-methylacetamido)benzoic acid, M.P. 312 C. (dec.).

(c) 5-(N-methylacetamido)-2,4,6-triiodomaleanilic acid [B; R is CHCON(CH R and R are H, Y is CH=CH-] can be prepared by hydrolysis of3-maleimido-2,4,6triiodo-N-methylacetanilide with dilute sodiumhydroxide.

wherein Y is a single bond, vinylene or an aikylene bridge having fromone to eight carbon atoms; R is (lower-a1- kanoyDNI-I,(lower-alkanoynNHcH (lower-alkanoyl) N(lower alkyl), lower alkoxy-loweralkanoyDNH, (1ower-alkoxy-lower-alkanoyl) N (lower-alkyl) HOOC-Y'CO-NH,

or HOOCY'CO--N(1ower-alkyl; R is hydrogen, lower-alkyl, orhydroxy-lower-alkyi; and R" is hydrogen or lower-alkyl.

2. A compound according to claim 1 wherein R is(lower-alkanoyl)N(1ower-a1kyl) and R is hydrogen.

3. N,N'-(2,4,6-triiodo-m-phenylene)diglutaramic acid, according to claim1 wherein R is I-I-OOCCH CH CH CNH,

R is H, R" is H and Y is CH CH CH 4. 2,4',6triiodo-3-(N-methylacetamido)-N-methy1- glutaranilic acid, according toclaim 1 wherein R is CH CON(CH R is CH R" is H and Y' is CHQCHQCHZ- 205. 2',4',6' triiodo-S'-(N-methylacetamido)-N-methy1- succinanilic acid,according to claim 1 wherein R is cn comcn R is CH R" is H and Y is CHCH 6. 2',4' -triiodo-3'-(N-methylacetamido) N ethylglutaranilic acid,according to claim 1 wherein R is CH CON(CH R is C2H5, R" is H and Y isCHZCHZCHZ.

7. 2',4',6-triiodo-3-(N-methylacetamido) 3,3,N trimethylglutaranilicacid, according to claim 1 wherein R is CH C0N(CH R is CH R" is H and Yis CH C(CH CH References Cited UNITED STATES PATENTS 2,895,988 7/1959Archer et a1 260-518 A LORRAINE A. WEINBERGER, Primary Examiner L. A.THAXTON, Asisstant Examiner U.S. Cl. X.R.

260243 B, 247.2 A, 247.2 R, 281, 326.3, 470, 471 A, 501.11, 516, 519,562 R; 424-5

